This application related to treatment of pulmonary and pleural fibrosis using inhibitors as hsp27.
Heat shock proteins (HSPs) are a set of highly conserved proteins whose expression is induced by different kinds of stress. Among the different HSPs, HSP27 is highly induced by different stresses such as high temperature, oxidative stress, or anticancer drugs (Beckmann et al., Science 1990; 248:850-4; Shashidharamurthy et al., J Biol Chem 2005; 280:5281-9) and is an ATP-independent chaperone. HSP27 is crucial in the control of apoptosis and can act at multiple points in the apoptotic pathways to ensure that stress-induced damage does not inappropriately trigger cell death (Bruey et al., Nat Cell Biol 2000; 2:645-52; Jego et al Cancer Lett, Nov. 13, 2010, E Pub ahead of print) probably because apoptosis and differentiation are two related processes. Recent reports involve HSP27 in the differentiation process (De Thonel et al., Blood 2010, 116:85-96). The cytoprotective function of HSP27 is also explained by its behavior as a molecular chaperone for other cellular proteins. Inappropriate activation of signaling pathways could occur during acute or chronic stress as a result of protein misfolding, protein aggregation, or disruption of regulatory complexes. The action of chaperones, through their properties in protein homeostasis, is thought to restore the balance. In association with HSP27 chaperone function, it has been demonstrated that HSP27 under stress conditions play a function in “proteins triage”; HSP27 may either stabilize or accelerate the degradation by the proteasome of certain “client” proteins to assure the survival of the cell (De Thonel et al 2010; Andrieu et al. Oncogene 2010, 29: 1883-1896; Parcellier et al., FASEB J 2006, 20: 1179-1181, and Parcellier et al., Mol Cell Biol 2003, 23: 5790-5802). The strong cytoprotective function of HSP27 together with the fact that the protein is overexpressed in most cancer combine to make this chaperone an interesting target to inactivate in cancer therapy. In this way, HSP27 depletion in different animals' models induces the regression of the tumors. The second generation oligonucleotide, OGX-427, is a specific inhibitor of HSP27 that can be administered in patients. Its anti-tumor effect has been demonstrated in many animal experimental models and it is now being tested in phase I/II clinical trials as a chemosensitizing agent in prostate cancer.
Epithelial-to-mesenchymal transition (EMT) occurs when epithelial cells transdifferentiate and acquire a myofibroblastic phenotype (Chapman H A., Annu Rev Physiol 2011; 73:413-35) TGF-β1, one of the most potent profibrotic mediators characterized so far, is also considered to be a master switch for the induction of EMT in various organs including the lung (Zavadil et al., Oncogene 2005; 24:5764-74). EMT is known to be involved in a variety of normal physiological processes including gastrulation, heart formation, and palate closure during embryogenesis but also in pathological conditions such as fibrosis, cancer invasion and metastasis. EMT describes a phenotypic change characterized by the loss of epithelial markers including E-cadherin and cytokeratin, the gain of mesenchymal markers such as α-smooth muscle actin (α-SMA), and the acquisition of cell migration properties. It has been reported that the cells migrate across the damaged basement membrane to the interstitial space, where they become activated myofibroblasts. (Mucsi et al. Acta Physiol Hung 2007; 94:117-31) The presence of α-SMA represents the most reliable marker of the myofibroblastic phenotype. The mechanisms leading to EMT are still poorly known.
Fibrosis generally is the formation of fibrous tissue as a reparative or reactive process. Pathological fibrosis is the undesirable formation of fibrous tissue that is associated with a disease state. In many instances, treatment options for fibrosis are presently limited or unavailable. For example, among fibrotic disorders, idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by a progressive and exaggerated extra-cellular matrix (ECM) accumulation and structural changes resulting in restrictive impairment of lung functions. The disease has no known etiology although some anti-cancerous drugs (e.g. bleomycin) are well known triggering events for the initiation of pulmonary fibrosis. (www.pneumotox.com. The drug-induced lung diseases. [Website] 2011 July, 2002 [cited 1996]).
The development of IPF is classically thought as an abnormal alveolar repair and myofibroblasts are the main cellular components responsible for the tissue remodeling that occurs during this repair. The pathological changes in IPF typically start in subpleural lung regions. (American Thoracic Society. Am J Respir Crit Care Med 2000; 161:646-64) This subpleural predominance of fibrosis is even a characteristic feature of IPF. To date, there is no clear explanation for this. Cool et al. suggest that myofibroblasts form a network, a “fibroblastic reticulum,” extending progressively from the pleura to the underlying parenchyma. (Cool et al., Am J Respir Crit Care Med 2006; 174:654-8. We recently reported that over expression of the fibrogenic cytokine transforming growth factor (TGF)-β1 in the pleural space not only induces progressive pleural fibrosis, but also is associated with abnormal collagen deposition within the subpleural lung parenchyma as observed in IPF. We demonstrated in this model that mesothelial cells undergo a transformation similar to what is observed during EMT in the presence of TGF-β and that these mesenchymal cells migrate and invade the lung parenchyma, suggesting that mesothelial cells may play a key role in IPF (Decologne, et al. J Immunol 2007; 179; 6043-6051).
US Patent Publication No. 2006/0003954 discloses an antisense inhalation therapy for IPF and other lung diseases in which the antisense is targeted to wild type COL1A.
U.S. Pat. No. 6,887,853 discloses treatment for fibrogenic disease using geldanamycin, which is an HSP90 inhibitor. No mention is made of HSP 27. Ryjanen et al. Eur J Pharmacol. 2008 Apr. 28; 584(2-3):229-36. Epub 2008 Feb. 14 discloses that geldanamycin increases HSP27 levels. HSP27 is also known for providing anti-inflammatory properties leading to increases in IL-10 and IL-12. (See US Patent Application No. 2001/004971). Since inflammation may be implicated in IPF and other forms of fibrosis, (See, Wilson et al, Mucosal Immunol. 2009 March; 2(2): 103-121), this combination of teachings would seem to suggest that reduction of HSP27 would be ill-advised in the treatment of fibrosis, including IPF.